PROJECT SUMMARY/ABSTRACT In 2017, more than 550,000 people became sick with a strain of tuberculosis (TB) that was resistant to rifampin and isoniazid, the two most potent drugs in the standard first-line TB regimen. Historically, treatment for patients with multidrug-resistant (MDR) TB has been long, toxic, and ineffective: on average, only 55% of treated patients were cured at the end of the conventional 18- to 24-month regimen, which included a daily injection for approximately eight months. In 2012 and 2013 regulatory authorities conditionally approved the first new TB drugs in fifty years, bedaquiline (BDQ) and delamanid (DLM), offering hope for more effective and less toxic MDR-TB treatment. In early 2019, based on the best available evidence, the World Health Organization (WHO) issued new guidelines for MDR-TB treatment. These guidelines included a new priority drug ranking for the composition of MDR-TB regimens, which established BDQ as an anchor of an injectable-free 18- to 24-month regimen and endorsed a standardized nine-month regimen containing an injectable. Although conventional injectable-free and shortened injectable-containing MDR-TB regimens represent enormous improvements, these new guidelines deferred guidance on a number of key questions for which evidence is lacking, leaving many national TB programs uncertain about how to implement MDR-TB treatment. For example, although recommendations guide the overall duration of treatment, there was no recommendation on the optimal duration of use of each drug. Moreover, there is no data on the safety or effectiveness of the regimen comprising the five top priority drugs. A lack of high quality MDR-TB cohort data also prevented guidance on other urgent questions, including (1) the safety and effectiveness of common off-label uses of BDQ and DLM, (e.g., co-administration and extended use of the drugs); and (2) whether BDQ or DLM could be substituted into the recommended nine-month regimen. In the absence of clinical trial data to address these questions, robust, valid causal inference from observational MDR-TB cohort data is of paramount importance to guaranteeing optimal treatment?and minimizing death, morbidity, and disease transmission?for MDR-TB patients throughout the United States and the world. The endTB initiative, implemented by our group, offers a unique opportunity to generate high-quality evidence to inform MDR-TB treatment and care. The endTB observational cohort of 2,600 MDR-TB patients treated with BDQ and/or DLM in 17 countries?the largest, systematically-collected prospective dataset of its kind. Detailed longitudinal data will permit robust analyses to inform lingering, critical questions, prioritized by the World Health Organization. We will exploit this unique resource, strong partnerships in high-MDR-TB-burden countries, and advanced expertise in epidemiologic methods to identify optimal MDR-TB regimens; inform optimal use of and adverse event monitoring for BDQ and DLM, and illustrate how combinations of robust, longitudinal data and novel methods can reduce these biases.